2-thio substituted-tetrahydro-halo-sulfamyl-quinazolinones



United States Patent 3,549,637 2-THIO SUBSTITUTED-TETRAHYDRO-HALO- SULFAMYL-QUINAZOLINONES Bola Vithal Shetty, Rochester, N.Y., assignor to Pennwalt Corporation, East Orange, NJ., a corporation of Pennsylvania N0 Drawing. Filed Mar. 11, 1968, Ser. No. 711,839 The portion of the term of the patent subsequent to July 29, 1977, has been disclaimed and dedicated to the Public Int. Cl. C07d 51/48 US. Cl. 260256.5 6 Claims ABSTRACT OF THE DISCLOSURE A 1,2,3,4-tetrahydro-halo sulfamyl 4 quinazolinone having diuretic properties, characterized by having in the 3-position a substituted or unsubstituted aryl or aralkyl group, and by having in the 2-position an alkylthio, aralkylthio, arylthio or cycloalkylthio, or cycloalkylalkylthio.

This invention relates to 1,2,3,4-tetrahydro-6-sulfamyl- 3-aryl or aralkyl-4-quinazolinone compounds having diuretic properties, and more particularly to such compounds substituted in the 7- position with halogen or haloalkyl and in the 2position with alkylthio, phenylthio, phenylalkylthio, cycloalkylthio, or cycloalkylalkylthio groups.

In applicants copending application Ser. No. 517,995, filed Jan. 3, 1966, now US. Pat. No. 3,360,518, there are disclosed and claimed compounds of the above type having a thioalkyl group, such as methylthiomethyl or benzylthiomethyl, in the 2-position. These compounds are effective diuretics.

Applicant found that the compounds of his application Ser. No. 517,995 have useful diuretic characteristics regardless of Whether there is a thioalkyl group or an alkylthio, phenylalkylthio, phenylthio or cycloalkylthio group in the -2- position.

In accordance with this invention 1,2,3,4-tetrahydro-7- halo or haloalkyl-6-sulfamyl-3-aryl or aralkyl-4-quinazolinone compounds have alkylthio, aralkylthio, arylthio, cycloalkylthio or cycloalkylalkylthio groups in the 2- position. These compounds are effective diuretics.

The preferred compounds of this invention have the formula:

or the pharmaceutically acceptable salts thereof; in which X is halogen or trifluoromethyl; Y is hydrogen or loweralkyl; R is hydrogen or loweralkyl; R is alkylthio, phenylthio, phenylalkylthio, cycloalkylthio, cycloalkyl- 3,549,637 Patented Dec. 22, 1970 alkylthio, or such groups having halogen, loweralkyl, amino, sulfamyl, or nitro groups substituted in the phenyl ring or in the cycloalkyl ring, or in the alkyl group; R and R are hydrogen, loweralkyl, loweralkoxy, loweralkoxyalkyl; x is hydrogen, loweralkyl, hydroxy, loweralkoxyalkyl, loweralkoxy, NH SO NH halogen or trifluoromethyl; y anr z are any of x, and n is an integer from 0-4.

In the above formula X is preferably chlorine or trifluoromethyl, but bromine and the other halogens are not precluded. R is preferably hydrogen, but loweralkyls such as methyl, ethyl, propyl, and isopropyl may be used. R is preferably loweralkylthio such as methylthio or lowercycloloweralkylthio such as cyclopropylmethylthio, or benzylthio. The halogen of the halogen substituted alkyl is chlorine or other halogen. The aryl or aralkylthio is preferably a monocyclic carbo cyclic aryl loweralkyl, e.g., 'benzylthio, x, y, and z may be any of the stated radicals in one or more of the ortho, meta or para positions. Preferably x is methyl in the ortho position, also where sulfamyl is used it is: preferably present in the meta or para position with methyl in the ortho position.

Specific suitable compounds of the above formula include 2-methylthi0-3-o-tolyl-6-sulfamyl-7-chloro-1,2,3,4-

tetrahydro-4-quinazolinone;

2-methylphenylthio-3-o-tolyl-6-sulfamyl-7-trifluoromethyl- 1,2,3,4-tetrahydro-4-quinazolinone 2-phenylthio-3 -o-tolyl-6-sulfamyl-7-chloro-1,2,3,4-

tetrahydro-4-quinazolinone 2-ethylphenylthio-3 -o-tolyl-6-sulfamyl-7-triflu oromethyl- 1,2,3,4-tetrahydro-4-quinazolinone;

2-ethylphenylthio-3 -o-tolyl-6-sulfamyl-7-chloro-1,2, 3 ,4-

tetrahydro-4-quinazolinone;

2-methylthio-3-o-tolyl-6-methylaminosulfonyl-7-chloro- 1,2,3,4-tetrahydro-4-quinazolinone;

2-methylthio-3 p-chlorophenyl -6-sulfamyl-7-chloro- 1,2,3 ,4-tetrahydro-4-quinazolinone 2-methylthio-3-o-tolyl-6-methylami:nosulfonyl-7-chloro- 1,2, 3 ,4-tetrahydro-4-quinazolinone;

2-methylthio-3-phenyl-6-sulfamyl-7-chloro- 1,2,3 ,4-

tetrahydro-4-quinazolinone;

2-methylthio-3- 2-methyl-3-ch1orophenyl) -6-sulfamyl- 7-chloro-1,2,3,4-tetrahydro-4-quinazolinone;

2-methylthio-3 -(p-chlorophenyl) -6-methylaminosulfonyl- 7 -chloro- 1 ,2,3,4-tetrahydro-4-quinazolinone;

Z-methylthio- 3- 2'-methylbenzyl -6-sulfamyl-7-chloro- 1,2,3,4-tetrahydro-4-quinazolinone;

2-phenylthio-3-o-tolyl-6-sulfamyl-7-chloro-1,2,3,4-

tetrahydro-4-quinazolinone;

2-p ropylthio-3 -o-tolyl-6-sulfamyl-7-chloro-1,2,3,4-

tetrahydro-4-quinazolinone;

Z-butylthio-3-o-tolyl-6-su1famyl-7-c[hloro-1,2,3 ,4-

tetrahydro-4-quinazolinone;

2-propylthio-3 -o-tolyl-6-sulfamyl-7-trifiuoromethyl- 1,2, 3 ,4-tetrahydro-4-quinazolinone;

2-butylthio-3-o-tolyl-6-sulfamyl-7-trifiuoromethyl- 1,2, 3 ,4-tetrahydro-4-quinazolinone;

2-benylthio-3-o-tolyl-6-sulfamyl-7-ehloro-1,2,3,4-

tetrahydro-4-quinazolinone;

2- 2,2,2-trifluoroethylthio -3 -o-tolyl-6-sulfamyl-7- chloro-1,2, 3,4-tetr ahydro-4-quinazolinone;

2-ethylthio-3-o-tolyl-6-rsu1famyl-7-chloro-1,2,3 ,4-

tetrahydro-4-quinazolinone;

1 N \(|}H'R2 N--(CH2) YHNOzS \C/ Q X Z 5 R1 R2 :0 y z X Y n H S'Ph 2-Me 4-F H 01 H o H SPh 2-Me 4-012; H 01 H 0 H SPh 2-Me 4-CF3 H 01 Me 0 H SOHzPh 2-Me H H 01 H 0 H SOHzPh 2-Me 3-01 H 01 H 0 H SOHzPh 2-Me H H 01 H 1 H SCHZPh 2-Me H H 01 H 2 H SCHzPh 2-Me 3-Me H 01 H 0 H soH2P11 2-Me 4-0H H 01 H 0 H SCHzPh 2 Me 4-OMe H 01 H 0 H SCHzPh 2-Me 4-NH2 H 01 H 0 H SCHzPh 2-Me 4-01 H 01 H 0 H SCHzPh 2-Me 4-F H 01 H 0 H soH21 n 2-Me 4-CF3 H 01 H 0 H SOHzPh Z-Me 4-01 H 01 Me 0 H SGHzPh 2-Et H H 01 H 0 H s- 431 2-Me H H 01 H 0 H SMe 2-Me H H o H o M H sQ-cm 2-Me H H 01 0 SOHzCHzl-"h 2-Me H H 01 0 H s Oman-Q 2-Me H H 01 o OMe H SCHzCHz--NH2 2-Me H H or H 0 NOTE: Me=Methyl; Et=Ethyl; Ph=PhenyL The following synthetic scheme is given to illustrate H the preparation of compounds of this invention. Other 01 N compounds than that shown can be prepared by modifica- W 1 NaOH tions well known to the art. Also compounds of this inven- H NO S N 201131 tion may be made by modifications of the method shown 2 2 in my application Ser. No. 517,995 as will also be H apparent. PREPARATION OF 2-METHYLTHIO-3-(O-TOLYL)- H 6 SULFAMYL-7-CHLORO-1,2,3,4-TETRAHYDRO- EH3 N 4-QUINAZOLINONE C1 A1013 C1 T CH8 N N Synthetic route Hmots 0/ HzNOzS \C/ II II 0 0 Ca Ca The other compounds of this invention can be made by 01 NH; (CHSCOM) 01- NHC0CH3 LCISOEH modification of ingredients and quantities of the above example as is Well understood by those skilled 1n the art. CH CH3 From pharmacology tests run on 2methylthio-3-o-tolyl- 6O 6 sulfamyl 7-chloro 1,2,3,4 tetrahydro-4(3H)-quin- C1 NHCOCHa azolinone and othenindications and analogy the compounds of this lnvention are efiective diuretlcs, saluretlcs, 132N028 CHa (KMnO and antihypertensives with low toxicity. For example, the following is a summary of the pharmacology on the above 2-methylthio compound. 01- NHCOGH:

SUMMARY 112N028 COOH A (a) Symptomatology and Acute LDSO in mice:

033 Oral1yLD50 1000 mg./kg. (48 hours) no symptoms at t 1000 mg./kg. 01 NH N=O=S Interperitoneal-LD50 316 mg./kg. (48 hours) some 2 h h d d d t t ypot ermia an ecrease spon aneous motor activity HzNOzS- 00011 at (b) Cardiovascular in dog: Doses intravenously up to 7 l mg./kg. were administered. There were no changes in cardiovascular system.

(c) Diuretic assay in rats: When administered by the oral route in initial assays measuring output of urine (ml./ kg.), Na+, and Cl- (meg/kg.) at 4 hours and 21 hours after drug administration, 8720-22 was found to promote Water and salt loss, has a rapid onset and prolonged action, and appears to have a potency on volume diuresis better than that of quinethazone.

The compounds of this invention when used in the same manner and in dosage amounts as for hydrochlorothiazide are safe and effective diuretics.

In the preceding specification the wherever given, are in degrees centigrade.

Various modifications of the structural formula on column 1 of the specification may be made, such as, for example, has been done for other tetrahydro-7-halo-6- sulfamyl-4-quinazolinones known to the art, without departing from the spirit of the invention which is concerned particularly with the aryl and alkaryl group on the 3- position, and thio groups in the 2-position.

Likewise, therapeutically effective salts of the compounds of the invention may be made by methods known to the art, and are useful diuretics. For example, the sulfamyl group will react with bases to give sodium, potassium or ammonium salts of the quinazolinone compound. The basic nitrogen of the quinazolinone can be reacted with acids such as hydrochloric, maleic, tartaric, and the acidic ion exchange resins such as carboxylic acid, phosphonic acid, and sulfonic acid cation exchange resins to give the therapeutically effective and nontoxic salts of the quinazolinone compound.

temperatures,

I claim: 1. A compound of the formula:

R f N (}3HR YHNO2S N-(OHzhQ C x z or pharmaceutically acceptable salts thereof; in which X is halogen or trifiuoromethyl; Y is hydrogen or loweralkyl; R is hydrogen or loweralkyl; R is loweralkylthio, loweralkylphenylthio, phenylloweralkylthio, lowercycloalkylthio, lowercycloalkylloweralkylthio, phenylthio, or said groups having halogen, loweralkyl, amino, sulfamyl or nitro substituted in the phenyl ring or in the ring of the cycloalkyl or in the alkyl group; R and R are hydrogen, loweralkoxy, loweralkyl, loweralkoxyloweralkyl; x is hydrogen, loweralkyl, hydroxy, loweralkoxy, loweralkoxyloweralkyl, NH sulfamyl, halogen, or trifluoromethyl; y and z are any of the members of x, and n is an integer from O4.

2. A compound of claim 1 wherein X is chlorine, Y is hydrogen, R is hydrogen, R is benzylthio, x is orthomethyl, both y and z are hydrogen, and n is 0.

3. A compound of claim 1 wherein X is chlorine, Y is hydrogen, R is hydrogen, R is methylthio, x is orthomethyl, both y and z are hydrogen, and n is 0.

4. A compound of claim 1 wherein X is chlorine, Y is hydrogen, R is hydrogen, R is chloromethylthio, x is ortho-methyl, both y and z are hydrogen, and n is 0.

5. A compound of claim 1 wherein X is chlorine, Y is hydrogen, R is hydrogen, R is benzylthio, x is orthotrifluoromethyl, both y and z are hydrogen, and n is O.

6. A compound of claim 1 wherein X is trifluoromethyl, Y is hydrogen, R is hydrogen, R is benzylthio, x is ortho-methyl, both y and z are hydrogen, and n is 0.

References Cited UNITED STATES PATENTS 4/1969 McLamore et al. on 260256.5 7/1969 Shetty 260256.5

US. Cl. X.R. 42479, 251

2223 UNITED STATES PATENT OFFICE CERTIFICATE OF CGRRECTION PatentNo. ,54 ,63 med DecemberZZ, 1970 Inventor( It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 9, change "1977" to read 1986 Signed and sealed this 12th day of September 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,JH. ROBERT GOTTSCHALK Attesting Officer Cummissioner of Patents 

